State-of-the-Art Review

Journal of Veterinary Emergency and Critical Care 18(3) 2008, pp 235245

doi:10.1111/j.1476-4431.2008.00307.x

Cardiac troponins
Scott M. Wells, DVM, DACVECC and Meg Sleeper, VMD, DACVIM (Cardiology)

Abstract
Objective: To review the use of cardiac troponins as biomarkers for myocardial injury in human and
veterinary medicine.
Data sources: Data sources included scientific reviews and original research publications.
Human data synthesis: Cardiac troponins have been extensively studied in human medicine. Finding an
elevated cardiac troponin level carries important diagnostic and prognostic information for humans with
cardiovascular disease. Troponin assays are used primarily to diagnose acute myocardial infarction in patients
with ischemic symptoms such as chest pain. However, elevated blood levels may be found with any cause of
myocardial injury.
Veterinary data synthesis: Several studies have shown that cardiac troponins are sensitive and specific for
myocardial damage in veterinary patients and may have utility in diagnosis and prognosis for certain disease
states. Human assays may be used in most animals due to significant homology in the troponin proteins
between species.
Conclusions: Cardiac troponins are sensitive and specific markers of myocardial injury although they do not
give any information regarding the mechanism of injury. They have redefined how acute myocardial
infarction is diagnosed in humans. Their use in the clinical management of veterinary patients is limited at this
time. Further prospective studies are warranted.
(J Vet Emerg Crit Care 2008; 18(3): 235245) doi: 10.1111/j.1476-4431.2008.00307.x

Keywords: heart disease, infarction, monitoring, myocardial injury

Introduction
Cardiovascular diseases are commonly encountered in
both human and veterinary medicine. Biological markers, or biomarkers, are tools used to identify high-risk
individuals, quickly and accurately diagnose disease
states, and determine treatment plans and prognoses.
While the term biomarker was first introduced in 1989,
a National Institute of Health group standardized the
definition in 2001 as a characteristic that is objectively
measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention.1,2
Biomarkers commonly used in the diagnosis of cardiovascular disease may include measurements taken from
blood samples, blood pressure, ECG recordings, radiographs, and echocardiograms. Cardiac troponins (cTn)
From the New England Animal Medical Center, West Bridgewater, MA
(Wells), and Assistant Professor of Cardiology, Section Chief, Cardiology,
Matthew J. Ryan Veterinary Hospital of the University of Pennsylvania,
Philadelphia, PA (Sleeper).
Address correspondence and reprint requests to:
Dr. Scott M. Wells, DVM, Veterinary Specialty Hospital of the Carolinas,
6405 Tryon Road, Cary, NC 27518.
E-mail: scottw@vshcarolinas.com
& Veterinary Emergency and Critical Care Society 2008

have a high sensitivity and specificity for myocardial

damage and are considered the biomarker of choice for
detection of cardiac cellular injury.36 The purpose of
this paper is to review cardiac troponins and their utility in human and veterinary medicine.

Physiology
Troponins are regulatory proteins that are part of the
contractile apparatus of skeletal and cardiac muscle
tissue. They are not present in smooth muscle tissue.
With the proteins actin and tropomyosin, they are part
of the thin filaments within the myofibrils and are essential for the calcium-mediated regulation of muscle
contraction. The troponin complex consists of 3 interacting and functionally distinct proteins (troponin I, T,
and C).7 Tissue-specific isoforms exist for each type of
troponin.8 Within the thin filament, tropomyosin dimers form a continuous chain along the groove of the
actin helix. The troponin complex lies at regular intervals along the filament. Tropomyosin acts to block the
myosin binding sites on actin. Each troponin protein
has specific functions that regulate muscle contraction.
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S.M. Wells & M. Sleeper

This paper focuses on troponin I and T due to their

specificity for cardiac injury.
Troponin C (TnC) is present in 2 isoforms. One isoform is present in fast-twitch muscle fibers and the
other is present in both cardiac and slow-twitch muscle
fibers. Homology between the cardiac isoform and 1 of
the skeletal muscle isoforms reduces the cardiac specificity of TnC and therefore limits its diagnostic usefulness in heart disease.9 Troponin C binds calcium to
initiate muscle contraction.
Multiple isoforms of troponin T (TnT) exist in skeletal
muscle. Cardiac troponin T (cTnT) has a molecular
weight of 37,000 Da.10 In human cardiac tissue 4 isoforms exist, but only 1 is characteristic of the adult
heart. The other 3 cardiac isoforms are expressed in
fetal tissue. The fetal isoforms may be re-expressed
during heart failure or in damaged skeletal muscle.
Troponin T attaches the troponin complex to tropomyosin and actin.8
Three isoforms exist for troponin I (TnI). Two are
present in skeletal muscle and the other is present only
in cardiac muscle. The cardiac isoform (cTnI), with a
molecular weight of 24,000 Da, is larger than the other
isoforms as it contains an additional 32 amino acid Nterminal peptide. The rest of the protein has greater
than 40% dissimilarity in its amino-acid sequence compared with skeletal muscle TnI.8,10,11 Unlike cTnT, cTnI
is not expressed in fetal skeletal muscle during development, nor after damage and regeneration in adult
skeletal muscle.12 Troponin I inhibits actomyosin ATPase and prevents the structural interaction of myosin
with actin-binding sites. The binding of calcium to
troponin C displaces troponin I and causes a conformational change in tropomyosin so that it no longer
interferes with myosin/actin binding and muscle contraction can occur.
Mutations in the genes encoding for cTnT and cTnI
cause hypertrophic cardiomyopathy in humans.13,14
Conversely, a knock out cTnI mouse model develops
acute heart failure at 18 days of age.15

Troponin Release
The troponin protein exists in 2 populations within the
cells. The majority of troponin is structurally bound
within the thin filaments of the contractile apparatus. A
small percentage of protein remains free in the cytosol.
This percentage is approximately 24% for cTnI and
68% for cTnT.16,17 Troponins are considered leakage
markers. Damage to cardiac myocytes resulting in loss
of membrane integrity causes the release of cTn into the
circulation. Apoptosis, a genetically programmed form
of cell death, does not result in loss of cell membrane
236

integrity and therefore will not cause leakage of

troponins.18
Troponin release kinetics are consistent with 2 separate intracellular populations. After acute cardiac injury, the cytosolic pool is released resulting in an early
rise in blood levels. This is followed by the slower release of structurally bound troponin that results in a
sustained elevation (see Figure 1).16,17,19 The half-life of
troponin and its complex in the circulation is about 2
hours.20 In humans with acute myocardial infarction
(AMI), cTn levels begin to rise 412 hours after the infarction and reach peak values at 1248 hours. The levels remain elevated for 710 days (cTnI) and 1014 days
(cTnT).10,11,21 A canine model of AMI showed release
times similar to those observed in clinical human patients although the peak was attained earlier (range 10
16 hours).22 This earlier peak was hypothesized to be
due to more rapid development of necrosis in the experimental situation. The sustained elevation of cTn for
several days after AMI is likely due to ongoing release
from damaged myocytes rather than impaired elimination.23 The exact mechanism for elimination of troponins is unknown but it is thought to involve clearance
by the reticuloendothelial system.24 There is also some
evidence that troponins may be broken down into small
fragments that could be renally excreted.25 Elevated
cTn levels indicate myocardial damage but do not provide any information regarding its cause.

Reversible Versus Irreversible Injury

There has been debate over whether or not cTn is released after reversible cardiac injury or if it is only
released following irreversible injury. Some investigators still believe cardiac troponin I release only results
from irreversible membrane injury. Reversible ischemia
after exercise stress testing in humans has not resulted
in cTn elevations.26 However, several studies have suggested that troponin I can be released in reversible ischemia. For example, Feng et al. showed in a porcine
model of ischemic heart disease that reversible ischemia was associated with release of cTnI. The source
of troponin is hypothesized to be from the free cytosolic
pool leaking through a reversibly damaged myocyte
membrane. This hypothesis is also supported by clinical observations of 2 protein release patterns in patients with unstable angina: an early transient pattern
and a persistent pattern.2729 Additionally, some studies
involving prolonged strenuous exercise have shown
transient cTn release that is speculated to be from the
cytosolic pool rather than structurally bound cTn.30,31
The observation that myocardial dysfunction found
during sepsis is reversible also supports the idea of
troponin release associated with reversible injury.32

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Cardiac troponins

However, at this time it is not possible to differentiate

which population of cTn is released so the debate continues.33 Also, the clinical significance is unknown.

Assays

Figure 1: Release of cardiac troponins during acute myocardial

infarction. After injury resulting in loss of sarcolemmal membrane
integrity, the free cytoplasmic troponins are released first followed
by a more prolonged release of the structurally bound troponin proteins. Reprinted from Antman EM. Decision making with cardiac
troponin tests. N Engl J Med 2002;346(26):2080, with permission.106

Troponin levels are determined using enzyme-linked

immunosorbent assays (ELISA). The difference in amino-acid sequences from skeletal muscle and cardiac
troponin I and T has allowed production of antibodies
specific for cardiac troponins in these assays.34,35 The
first assays for detection of cTn were developed in the
late 1980s. These assays have evolved dramatically
since their introduction with greater sensitivity and
improved precision. The turnaround time for results
has also decreased from several hours to a few minutes.
Point-of-care assays now exist that may be run bedside
or in the field. There are multiple assays available from
a variety of manufacturers for cTnI. This has led to
some confusion regarding interpretation of results. The
assays are not standardized so manufacturers may design the tests using proprietary antibodies that target
varying amino-acid sequences on the cTnI molecule. In
the bloodstream, cTnI can be modified or complexed to
other proteins, such as cTnC, and the antibodies used in
the assays may have differing specificity for each circulating form of cTnI.36,37 There exists no gold standard
assay for cTnI at this time. Comparison studies using a
number of analyzers have concluded with the recommendation that, until assays are standardized, reference
ranges should be established for each individual assay.
Also, absolute values obtained from different assays
cannot be compared.36,38,39 Serum, heparinized plasma,
or whole blood may be sampled depending on which
cTnI assay is used. Studies in dogs have shown that
cTnI levels do not significantly change in serum stored
at room temperature over a 5-day-period nor in serum
that has undergone up to 5 freezethaw cycles.40,41 Only 1 manufacturer produces an assay for cTnT that
eliminates interassay comparison issues for this protein. The first generation cTnT assays used an antibody
that cross-reacted with skeletal muscle troponin T,
thereby decreasing its specificity for cardiac injury.42,a
Subsequent generations of cTnT assays have replaced
this antibody with 1 more specific for cTnT, thereby
eliminated the false positives related to skeletal muscle
leakage.35 Although sensitivity of the assays for
troponins has improved over the years, concern remains about their precision at low levels.43 The occurrence of false positive troponin results due to
interfering substances in the blood has also been reported. Rheumatoid factor, excess fibrin, heterophile
antibodies, hemolysis, lipemia, elevated alkaline phosphatase, and immune complex formation have all been

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S.M. Wells & M. Sleeper

implicated as causes of false positive troponin results. If

a false positive result is suspected and instrument malfunction is ruled out, then repeating the test on a recentrifuged or new blood sample is indicated. The use
of blocking reagents for substances such as rheumatoid
factor and heterophile antibodies may decrease false
results due to these interferences. Alternatively, because
the problem of interference is assay dependent, the
sample may be tested using a different manufacturers
assay.44
While some assays have been specifically validated
for use in veterinary medicine, it is generally believed
that human assays for cTn can be used to measure
blood levels of cardiac troponins I and T in most species
encountered.5,6,45,b,c Recently, the genes for canine and
feline cTnI were sequenced proving the protein structure is highly conserved among these species. Homology between canine and feline genes and humans was
95% and 96%, respectively. In the region targeted for
detection by most assays, dogs and cats were identical
to each other and humans differed from dogs and cats
by only 1 amino acid.45 Other studies have shown that
cTnI and cTnT from many mammalian species can be
measured using human assays and that these proteins
are specific for myocardial injury.5,6 Species studied include dogs, mice, rats, pigs, monkeys, sheep, rabbits,
horses, and cows. However, cardiac troponin I measurements appear less useful in birds and useless in fish
due to a smaller ratio of cardiac to skeletal muscle reactivities in these species.6
Normal values for cardiac troponin I and T have been
reported in veterinary species.4653 Although each assay
must have its own range established, reports of normal
values for healthy animals have correlated closely.39
Most normal animals have cTn levels below the threshold of detection for current assays.4653 Normal cTnI
ranges for dogs are reported at o0.030.07 ng/mL with
a median of 0.02 ng/mL.46 For cTnT all normal dogs
had levels below the threshold for detection by the assay.48,51 Cats have ranges of o0.030.16 ng/mL.46 A report of normal levels in adult horses including pastured
and race trained Thoroughbreds demonstrated a mean
cTnI of 0.047  0.085 ng/mL.47 There was no significant
difference in cTnI concentration between horses undergoing race training and pastured horses. However, as
already stated, normal ranges must be run on each
system and result comparison using different systems
is not possible.39

Myocardial Infarction
Cardiovascular disease is the leading cause of morbidity and mortality in humans in the United States.54 The
primary role of cardiac troponin testing in human
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medicine is for diagnosis of ischemic heart disease such

as myocardial infarction (MI). MI refers to myocardial
cell death due to ischemia.55 In humans, MI occurs after
the rupture of an atherosclerotic plaque in the coronary
arteries resulting in platelet aggregation, clotting, and
either large vessel occlusion or distal embolization.56
For years, according to the World Health Organization
(WHO), MI has been defined as a syndrome requiring
at least 2 of 3 diagnostic criteria.57 These criteria included an appropriate clinical history and presentation,
ECG changes typical for MI, and elevated cardiac enzymes, such as total creatine kinase (CK) and its myocardial form (CK-MB), lactate dehydrogenase, and
aspartate aminotransferase. Total CK, lactate dehydrogenase, and aspartate aminotransferase have poor specificity for cardiac damage.55,58 While CK-MB is more
specific than total CK for injury to the heart, it is not as
cardiac-specific as the troponins.3 CK-MB levels also
return to baseline within 48 hours so late diagnosis of
MI is not possible with this marker, whereas troponin
levels remain elevated for approximately 10 days.59 Because humans may not have typical clinical signs and
ECG changes may be nondiagnostic, a joint committee
of the European Society of Cardiology and the American College of Cardiology (ESC/ACC) developed a
new definition for the diagnosis of MI in 2000.55 This
new definition was based predominately on the use of
biomarkers such as the troponins in the diagnosis of MI
(see Table 1). Any elevation of troponin above the reference range is considered abnormal. In humans, the
reference ranges for troponins are set at the 99th percentile of the control group (3 SD from the mean). Owing to the release kinetics of troponins, it is possible that
patients presenting within hours of an acute ischemic
event may not have elevated cTn levels. It is therefore
recommended that samples be taken at the time of admission, at 69 hours, and again 1224 hours after presentation.55 In situations where an early diagnosis is
needed, a biomarker that rises rapidly, such as myoglobin or CK-MB, in addition to the later-rising troponin
may be used.55 Based on the new definition and use of
Table 1: ESC/ACC criteria for diagnosis of myocardial infarction in humans proposed in 200055
One of the following 2 criteria may be used to diagnose MI:
1. Typical rise and fall of biochemical markers such as troponin or CK-MB
with at least 1 of the following:
 Ischemic symptoms (e.g., chest pain)
 Development of pathological Q waves on the ECG
 ECG indicative of ischemia (ST-segment changes)
 Coronary artery intervention (e.g., angioplasty)
2. Pathological findings of myocardial infarction
ESC/ACC, European Society of Cardiology/American College of Cardiology; MI, myocardial infarction; CK-MB, creatine kinase-MB.

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Cardiac troponins

Table 2: Reported causes of elevated cardiac troponins in humans and animals

Humans11,30,31,55,70,7278
Ischemic heart disease (e.g., myocardial infarction, unstable angina)
Blunt chest trauma resulting in contusions
Trauma during cardiac surgery or myocardial biopsy
Electrical cardioversion, pacing, and implantable cardioverter defibrillator
firings
Congestive heart failure
Hypertrophic cardiomyopathy
Hypertension
Sepsis
Rhabdomyolysis with cardiac injury
Extreme exercise (marathon runners or Ironman triathlon competitors)
Abnormal cardiac rhythms (prolonged tachycardias, atrial fibrillation)
Animals22,40,4853,7988,d,gm
Models of myocardial infarction
Congestive heart failure
Canine dilated cardiomyopathy
Mitral valve disease
Pericardial effusion
Feline hypertrophic cardiomyopathy
Gastric dilatation-volvulus
Toxins (e.g., doxorubicin, cantharadin)
Babesiosis
Feline hyperthyroidism
Renal insufficiency

highly sensitive troponin assays, many patients are

now diagnosed with MI who would not have had that
diagnosis using the previous WHO criteria. In a study
of 2181 patients with chest pain presenting to an emergency department, the implementation of the new definition resulted in an increase in the diagnosis of MI by
195%.60 Another study of patients with chest pain presenting to an emergency room showed that cardiac
troponin testing was highly sensitive for the early detection of myocardial injury.61 In addition, this study
suggested that a negative troponin test at admission
and 6 hours after the onset of symptoms was associated
with a low-risk of a heart-related event and patients
could be discharged early from the hospital. This provides strong evidence that troponin testing is effective
for rapid triage of emergent patients with chest pain.

Prognosis
Cardiac troponins also have a role in establishing prognosis. With MI, any troponin level above the reference
range is associated with an increased risk of adverse
events in both the short- and long-term.6164 It has also
been shown that the magnitude of troponin level elevation correlates with risk of future cardiac events or
death and aids the identification of patients with greater disease severity who may benefit from more aggressive therapy.6466 In fact, the size of the infarcted area

Hypotension/hypovolemia
Renal failure
Drug toxicity (e.g., doxorubicin)
Snake envenomation
Coronary vasospasm
Inflammatory disease involving the heart (e.g., myocarditis, pericarditis)
Percutaneous coronary intervention
Pulmonary embolism and pulmonary hypertension
Infiltrative disease of the myocardium (e.g., sarcoidosis, amyloidosis)
Sympathomimetic activity (e.g., cocaine use, massive catecholamine
release such as in head trauma or stroke)
Cardiac transplantation
Chronic obstructive pulmonary disease
Ehrlichiosis
Third degree heart block
Arrhythmogenic right ventricular cardiomyopathy in Boxers
Blunt chest trauma
Subaortic stenosis
Sepsis
Aortic insufficiency jet lesions
Endurance exercise in dogs and horses
High dose isoproterenol

may be predicted based on peak cTnI levels or cTnT

levels at 72 hours.6769 In addition, elevations of cTn
have prognostic significance in other forms of cardiovascular disease such as heart failure and pulmonary
thromboembolism.70,71

Other Causes of cTn Elevations in Human and

Veterinary Medicine
MI is a clinical diagnosis and cannot be made based on
troponin elevations alone. While cTn elevations indicate myocardial injury, they do not give any information as to the mechanism of injury. Serial samples may
aid in diagnosis because acute injuries such as MI will
have a typical rise and fall of serum values whereas
other cardiac diseases such as chronic congestive heart
failure may result in persistent, relatively lower
troponin elevations.56 Troponin levels can rise with
very small amounts of myocardial cell necrosis and
most studies show that cTnI levels are more sensitive
than cTnT levels at detecting cardiac damage.53,61 There
exist many causes of cardiac injury and therefore elevations in cTn (see Table 2).

Trauma
Direct trauma to the heart can result in cTn elevations.
This may be secondary to mechanical injuries such as

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cardiac surgery, catheterization procedures, myocardial

contusions from blunt chest trauma, electrical injuries occurring during cardioversion, ablation procedures, or
defibrillation.55,72,89 Human studies of patients with chest
trauma have proven cTnI testing to be valuable in ruling
out significant blunt chest injury leading to cardiogenic
shock, severe arrhythmias, or structural damage related
to trauma.73,89 The negative predictive values of cTnI in
these 2 studies were 93% and 94%. When combined with
a normal ECG, these values increased to 100%. This allows patients that normally would be monitored in the
hospital for 13 days to be discharged early. Elevations of
cTn have also been shown to be sensitive in detecting
cardiac injury in dogs and cats with blunt chest trauma,
although further studies are needed to determine if cTn
levels can aid in the clinical management of veterinary
patients with chest trauma.53,79,80

Infection and Inflammation

Myocardial dysfunction and cTn elevations during sepsis
are common.74,90 While the exact mechanisms are unknown, cardiac oxygen demand exceeding supply, septic
microemboli, toxic effects from bacterial endotoxins, and
cardiac depressant effects from cytokines such as tumor
necrosis factor-a are postulated mechanisms.74,91 Ischemia and reperfusion injury secondary to microvascular dysfunction may also be involved. In humans,
elevated cTn values during sepsis are associated with
left ventricular dysfunction.74 Cardiac troponin I elevations are also present with myocarditis.75 Little work has
been done to evaluate cTn levels during sepsis in veterinary medicine. A study involving septic foals showed
that cTnT values were significantly elevated compared
with healthy foals but there was no difference in levels
among survivors compared with nonsurvivors.81
Although not common, canine babesiosis can cause
cardiac lesions such as epi- and endocardial hemorrhage, inflammatory cell infiltrate, myocardial fiber necrosis, and pericardial effusion.82 These changes are
thought to be related to the severe systemic inflammatory response and anemic hypoxia. Elevations in cTnI
can be used to determine cardiac involvement in babesiosis and there is an association between cTnI levels and
clinical severity and mortality. A study of dogs in Brazil
naturally infected with Ehrlichia canis showed that 44%
of patients had elevated cTnI concentrations without
clinically apparent heart disease suggesting myocardial
involvement.d

Primary Heart Disease and Heart Failure

Cardiac troponins can be released during acute and
chronic congestive heart failure in humans and veter240

inary patients. The evolution of the clinical entity of

heart failure is accompanied by cardiac remodeling as a
result of hypertrophy of myocardial myocytes, death of
cardiac myocytes consisting of both cell necrosis and
apoptosis, and formation of fibrotic replacement tissue.
These are all a consequence of the complex interaction
between mechanical, neurohumoral, inflammatory, and
ischemic alterations within the myocardium.50,76,92,93
Both cTnI and cTnT may be elevated in humans with
heart failure due to left ventricular dysfunction and
these patients have a worse prognosis than those with
normal cTn levels.71,94 Troponin levels often return to
normal after successful treatment of the acute episode,
suggesting that cTn levels can be used to monitor the
clinical course of disease.71
Several studies in veterinary medicine have shown
that cTn levels can be elevated in primary heart diseases.4852 Hypertrophic cardiomyopathy (HCM) in
cats can cause intramural coronary artery disease leading to microscopic areas of ischemia, and myocardial
hypertrophy with cellular necrosis and cTn release into
the circulation.95,96 Although cats with mild HCM may
have normal cTnI levels, a study has shown that cats
with moderate to severe HCM with and without heart
failure have significantly higher levels of circulating
cTnI than normal cats.49,e A weak correlation existed
between cTnI concentrations and ventricular wall thickness. Furthermore, cats with HCM and heart failure
had levels significantly higher than those without heart
failure suggesting that cTnI levels may be used to
differentiate cats with cardiac and noncardiac causes of
respiratory distress.49,f
Cardiac troponin levels can identify dogs with mitral
valve disease (MVD), subaortic stenosis (SAS), and dilated cardiomyopathy (DCM) and the cTn level may
correlate with severity and prognosis.48,5052 One study
showed that by using the International Small Animal
Cardiac Health Councils heart failure classification
method, dogs with class II and IIIA heart failure had
significantly higher blood levels of cTnI than normal
dogs and dogs with class IA and IB heart failure.50 Using a cut-off cTnI concentration of 0.095 ng/mL, this
study identified dogs with class II or worse heart failure
with a sensitivity of 96% and specificity of 88%. Another study which evaluated 93 dogs with heart disease
(MVD, DCM, and SAS) showed that 47% of the dogs
had elevated cTnI levels and there was a significant
difference in cTnI concentration between dogs with
heart disease and the normal control population.52 In
the dogs with cardiomyopathy, prognostic significance
was found using a cut-off cTnI level of 0.2 ng/mL. Median survival with a level 40.2 ng/mL was 112 days
while dogs with levels o0.2 ng/mL had a median survival of 357 days. A correlation was also found between

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found that cTnI levels did not differentiate the etiology

in these cases.k Clearly further research with larger case
numbers is warranted.

heart chamber size and cTnI level in that study. Unfortunately, as described above, cTnI comparisons between different machines are not possible and limit the
use of this data.39 Similar studies in dogs using the
cTnT assay have shown elevated levels in approximately 30% of patients with acquired heart disease, consistent with studies that show cTnI is more sensitive than
cTnT.48,51
Boxer dogs with arrhythmogenic right ventricular
cardiomyopathy are reported to have cTnI levels significantly higher than control Boxers and non-Boxers.g
This is likely due to persistent membrane leakage from
myocarditis and myofiber degeneration found with this
disease.97
Dogs with third degree atrioventricular block have
also been found to have significantly elevated cTnI
concentrations.h The underlying cause of the dysrhythmia, such as fibrosis or inflammation, or the hypoxic
damage secondary to decreased perfusion are thought
to be potential reasons.
Little research involving cardiac disease and cTn levels has been performed in horses but there are reports
of elevated cTnI levels in horses with ventricular arrhythmias. Reports of 2 horses with ventricular
tachycardia showed that 1 had a ruptured aortic jet lesion and another had severe myocardial necrosis of
unknown cause.83,98 Toxicities such as Streptococcus spp.
myositis, red maple leaf ingestion, white snakeroot
poisoning, and cantharadin intoxication from blister
beetles have been reported to cause elevated cTnI in
horses but the significance of this is unknown.i,j Additionally, cTnI elevations were noted in some endurance
horse athletes competing at the 50 and 100 mile distances, however, the significance was unclear.84

Cardiomyopathy secondary to chemotherapy, particularly anthracyclines such as doxorubicin, is irreversible

and usually fatal. Development of cardiomyopathy is
related to the cumulative dose throughout the course of
chemotherapy. Clinical signs of cardiac disease may be
delayed, occurring after chemotherapy is finished.86 In
humans, cardiac troponin elevations in patients who
have received chemotherapy can be predictive for the
development of cardiac toxicity and decreased left ventricular function.77,100 Cardiac TnT became elevated in 2
dogs with lymphoma undergoing doxorubicin therapy
and 1 of these dogs died from a suspected cardiac
event.48 Peak elevations of cTnT were noted in 1 dog 3.5
weeks after receiving a cumulative dose of 150 mg/m2
and in the other dog 2 weeks after a cumulative dose of
180 mg/m2. These dogs did not have ECG or echocardiographic evidence of cardiac disease at earlier time
points. A retrospective study showed that cTnI levels
were elevated in 32 of 44 dogs during doxorubicin chemotherapy for lymphoma and osteosarcoma, but the
elevations did not predict development of cardiac disease based primarily on physical exam findings and
thoracic radiographs.86 In dogs with elevated cTnI levels that developed clinical heart disease, the cTnI elevation preceded recognition of cardiac dysfunction.
Further prospective studies are needed to determine if
troponins will be useful in the clinical management of
patients receiving chemotherapy.

Pericardial Disease

Exercise

Pericardial disease has been shown to cause elevations

in troponin levels in both humans and veterinary patients. Acute pericarditis in humans commonly causes
troponin elevations.99 The release is thought to be secondary to epicardial inflammation. Decreased coronary
perfusion during tamponade may also be the cause of
troponin release. Two studies have shown that dogs
with pericardial effusion have significantly higher cTnI
levels than normal dogs.85,k One of these studies suggested that cTnI levels may be utilized to differentiate
idiopathic pericardial effusion and pericardial effusion
due to hemangiosarcoma. This study prospectively
evaluated 26 dogs in which a definitive cause of pericardial effusion was identified. A significantly higher
cTnI level was found in dogs with hemangiosarcoma
versus dogs with idiopathic pericardial effusion.85 However, a separate prospective study involving 20 dogs

Many studies have reported elevated cTn levels in humans after extreme endurance exercise such as marathons and Ironman triathlons.30,31,101 A study
evaluating competitors in the 1994 Hawaii Ironman
Triathlon showed that some athletes had elevated cTnT
and cTnI levels and echocardiographic abnormalities
following the race.31 It was not determined whether
this represented temporary or long-term cardiac damage although it was believed to be transient based on
other studies involving Ironman competitors showing
echocardiographic abnormalities returning to normal
after 48 hours. Moreover, the athletes continued to
compete in these strenuous competitions. Troponin release in these cases may be from the cytosolic pool
rather than structurally bound troponin. A report on
serum chemistry alterations in Alaskan sled dogs during endurance exercise showed elevations in cTnI, with

Chemotherapy

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S.M. Wells & M. Sleeper

highest levels attained after running 160 km.l Cardiac

troponin I elevations were also noted in endurance
horses (as mentioned previously).84

Pulmonary Thromboembolism
Pulmonary thromboembolism (PTE) and pulmonary
hypertension cause pressure overload of the right ventricle due to increased pulmonary arterial resistance.
The resultant increase in right ventricular pressure
leads to decreased myocardial perfusion and oxygen
supply. These changes, in addition to hypoxemia
with pulmonary thromboembolism, can cause cardiac
damage and cTn leakage.70 Pulmonary embolism
has also been associated with right ventricular infarction, confounding the interpretation of elevated cTn
in these patients.102 However, patients with PTE and
elevated cTn have a worse prognosis than those without cTn elevation.70 Troponins have not yet been evaluated in veterinary patients with PTE or pulmonary
hypertension.

Feline Hyperthyroidism
Cats with hyperthyroid disease commonly have cardiovascular abnormalities. These may include tachycardia,
myocardial
hypertrophy,
hypertension,
arrhythmias, and congestive heart failure, particularly
if primary cardiomyopathy is concurrently present. In a
study of 23 hyperthyroid cats, 11 had elevated levels of
cTnI before treatment with radioactive iodine.87 Cats
with elevated cTnI had significantly thicker interventricular septums; however, this increased thickness was
still considered to be within the normal feline reference
range. Although not reaching statistical significance,
the cats with cTnI elevations also tended to have higher
T4 levels. Six months after treatment, only 3 cats still
had cTnI elevations, suggesting the resolution of continued myocyte damage in the majority of these cats.
The mechanism of troponin release was not determined
although it was speculated to result from myocardial
cell damage associated with intramural coronary ischemia or from the physiological effects of excess thyroid hormone.

Gastric Dilatation-Volvulus
Cardiovascular complications resulting from gastric dilatation-volvulus (GDV) are common. These include
shock, ischemia and reperfusion injury, and arrhythmias. It has been shown that dogs with GDV
can have myocardial degeneration, and necrosis.40 Two
studies in veterinary medicine have assessed the use of
cTn measurement to identify myocardial damage in
242

dogs with GDV.40,53 One study evaluated 85 dogs with

GDV and found elevated cTnI and cTnT in 87% and
51% of patients, respectively, and all dogs that died
(19%) had elevated cTnI levels.40 Peak cTnI levels were
found 4872 hours after surgery. Cardiac troponin I and
cTnT levels were predictive of outcome. Results of the
second study were similar with increased cTnI and
cTnT values in 93% and 57% of patients, respectively.53
Peak troponin levels were found 2448 hours after surgery and all dogs that died (21%) had elevated cTnI
levels. These studies suggest that cTn evaluation in
dogs after GDV surgery may identify a group of patients requiring more intensive monitoring and therapy
and may provide useful prognostic information as well.

Renal Failure
Cardiac disease is a common cause of death in humans
with end-stage renal disease.78 Chronic elevations of
troponins exist in approximately 50% of patients with
chronic renal insufficiency.103 Although the exact cause
is unknown, many mechanisms for these elevations
have been proposed including silent myocardial necrosis, ventricular hypertrophy, and impaired renal clearance.76 Troponin T is more commonly associated with
elevations during renal disease with 1 study showing
82% of patients with cTnT elevations compared with
only 6% with elevated cTnI.104 However, evidence
suggests that cTnT fragments accumulate in the
bloodstream due to poor renal clearance making interpretation in these patients difficult.25 Therefore, without knowledge of baseline levels, cTnI may be more
specific for acute cardiac injury than cTnT in the face of
renal failure. Regardless of cause, elevations of troponin
I and T in patients with renal disease and patients on
hemodialysis were found to be indicators of mortality.104,105 In a veterinary study, 11 of 14 cats and 29 of 36
dogs with moderate to severe azotemia due to renal
insufficiency had elevated cTnI levels.m

Conclusion
Owing to their high sensitivity and specificity for myocardial damage, evaluation of cardiac troponin levels
has proven valuable and is firmly established in the
management of human patients with cardiac disease. In
veterinary medicine, troponin measurements have been
shown to have the potential to be sensitive indicators of
myocardial injury due to both cardiac and noncardiac
disease processes, although their role in clinical practice
remains to be determined. Perhaps future studies will
provide further evidence supporting the use of troponins in diagnosis, prognosis, and management of diseases encountered in veterinary medicine.

& Veterinary Emergency and Critical Care Society 2008, doi: 10.1111/j.1476-4431.2008.00307.x

Cardiac troponins

Self-Quiz Questions
1. Which troponin may not be used to detect myocardial injury and why? Answer: Cardiac troponin C. Its
structure is homologous to an isoform of troponin C found
in skeletal muscle, therefore reducing specificity for
cardiac injury.
2. Which is true regarding cardiac troponin I assays?
(a) There exists a gold standard assay for cTnI.
(b) Each assay targets the same sequence of the
cTnI molecule.
(c) Results from different assays may be compared.
(d) The reference range is the same for all commercially available assays.
(e) Human assays may be used in veterinary
medicine.
Answer: e
3. List 10 disease states that may cause elevated cardiac
troponin levels in veterinary patients.
Answers: see Table 2.
4. An elevated cardiac troponin level indicates which
of the following:
a. Myocardial infarction.
b. Heart failure.
c. Myocardial injury.
d. Cardiac hemorrhage or inflammation.
Answer: c. Cardiac troponins indicate myocardial injury but do
not give any information regarding the mechanism of injury.

Footnotes
a

Dameron GW, Beck ML, Brandt M, et al. Tissue species specificity of two
generations of cardiac troponin T immunoassays. Clin Chem
1997;43:S192 (abstract).
Adin DB, Berger KD, Engel C, et al. Cardiac enzyme concentrations in
normal dogs and cats using a bedside analyzer. Proc 22nd ACVIM
2004;877 (abstract).
Oyama MA, Solter PF. Validation of a commercially available human
s
immunoassay (AccuTnI , Beckman Coulter Inc.) for the measurement of
canine cardiac troponin-I. Proc 21st ACVIM 2003 (abstract).
Diniz P, deMorais H, Schwartz D, et al. Cardiac troponin I in dogs
naturally infected by Ehrlichia canis. Proceedings 23rd ACVIM 2005
(abstract).
Herndon WE, Sammarco CD, Schrope D, et al. Prospective evaluation of
plasma cardiac troponin I concentration in cats with mild hypertrophic
cardiomyopathy. Proc 22nd ACVIM 2004 (abstract).
Herndon WE, Schrope D, Drobatz KJ, et al. Plasma cardiac troponin
I concentration in cats with cardiac and noncardiac causes of respiratory
distress. Proc 22nd ACVIM 2004 (abstract).
Baumwart RD, Orvalho J, Meurs KM. Elevated serum cardiac troponin
I levels in Boxer dogs with arrhythmogenic right ventricular
cardiomyopathy. Proc 24th ACVIM 2006 (abstract).
Church WM, Oyama MA, Sisson DD, et al. Troponin I elevations in dogs
with third degree atrioventricular block. Proc 24th ACVIM 2006
(abstract).
Foreman JH, Oyama MA, Tennent-Brown BS, et al. Cardiac troponin-I
plasma concentration in normal horses and in horses with arrhythmias
and toxicities. Proc 23rd ACVIM 2005 (abstract).
Holbrook TC, Panciera RJ. Biochemical evidence of cardiac injury in
horses with cantharidin toxicosis. Proc 24th ACVIM 2006 (abstract).

Linde A, Summerfield N, Clifford CA, et al. Cardiac troponin I levels in

pericardial effusion and peripheral blood from dogs with neoplastic
versus non-neoplastic etiologies. Proc 21st ACVIM 2003 (abstract).
McKenzie EC, Hinchcliff KW, Williamson KK, Davis MS. Serum
chemistry alterations in Alaskan sled dogs during five successive days
of prolonged endurance exercise. Proc 24th ACVIM 2006 (abstract).
Rishniw M, Porciello F, Herndon WE, et al. Cardiac troponin
I concentrations in dogs and cats with renal insufficiency. Proc ECVIMCA:Barcelona 2004;197.

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